Increased levels of apolipoprotein B (apoB) in human plasma are associated with an increased risk of coronary artery disease. ApoB is the major protein component of human plasma chylomicrons, very low density (VLDL) and low density (LDL) lipoproteins. ApoB functions to transport cholesterol, cholesteryl esters, triacylgly-cerols and phospholipid in the circulation to specific tissues. This tissue interaction is mediated by the binding of lipoproteins, to specific membrane receptors. ApoB also mediates the binding of lipoproteins to heparin-like mucopolysaccharides of the arterial wall which may promote atherosclerosis. There are four plasma species of apoB: B-100 (Mr=550,000), B-74 (Mr=407,000) and B-26 (Mr=44,000) of hepatic-derived VLDL and LDL, and B-48 (Mr=246,000) of intestinal chylomicrons. Their structure, function, and metabolic relationships remain obscure. Preliminary findings show that cleavage at thrombin-sensitive sites in B-100 liberates fragments with molecular weights identical to B-74, B-26 and B-48 apoproteins. It is proposed that the B-100 is a structural precursor to B-74, B-26 and B-48 apoproteins. To test this hypothesis, the enzymically-derived fragments of B-100 will be compared to the B-74, B-26 and B-48 apoproteins of plasma for structural and functional homologies. This will be accomplished using monoclonal antibodies, peptide-maps, NH2-terminal sequence determinations, amino acid analyses, and functional assays of both heparin- and cell receptor-binding. It is anticipated that these studies will show a role for serine-proteases in the biological control of lipid metabolism and should help elucidate the structure, function and metabolism of apolipoprotein B.